The Goldilocks Method for Curing Autism

Combining two bad mutant genes produces neurons that're just right.

THE STUDY“Inhibition of p21-Activated Kinase Rescues Symptoms of Fragile X Syndrome in Mice.” By Mansuo L. Hayashi et al., published in the July 3, 2007, issue of Proceedings of the National Academy of Sciences.

THE MOTIVE If a gene mutation hinders brain development, the resulting mental retardation is usually considered irreversible. Symptoms can be treated, but the broken wiring cannot be fixed. Or can it? A startling new study of fragile X syndrome—the most common cause of inherited mental retardation as well as a leading genetic cause of autism—indicates that not only can malformed nerves be repaired but that behavior can be restored to normal, or nearly so. The research was done with two strains of mutant mice, but the neuroscientists involved say the results point to a target for drugs that could potentially repair analogous damage in humans.

THE METHODS Nobel Prize winner Susumu Tonegawa and postdoc Mansuo Hayashi did not set out to fix fragile X. As researchers at the Picower Institute for Learning and Memory at MIT, they were simply interested in learning how mice acquire memories. But then Hayashi created a mouse with a mutation in a gene called PAK, which codes for an enzyme called p21-activated kinase that helps build nerve connections in the brain. When Hayashi injected a mutant gene for PAK into mouse embryos and later killed the adult mice and dissected and examined their brains, she discovered that the animals’ dendritic spines—branched stalks that receive input from neighboring neurons—were short, fat, and sparse. When she attached two electrodes to the neurons—one to stimulate the nerve, the other to record the response—she discovered that the neurons’ firing rate was abnormally high.

These traits are diametrically opposite to the traits that show up in fragile X, a condition in which a mutation silences the gene called FMR1, or fragile X mental retardation 1. Both mice and humans with a silenced FMR1 gene have malformed neurons: Spines on their dendrites are longer, thinner, and more numerous than normal, and they also transmit weaker electric signals. Behavior is also affected. Up to 33 percent of people with fragile X are autistic, most are mentally retarded, and they may be overanxious, hyperactive, or engage in repetitive behaviors like hand flapping. Mice with the same mutation are also hyperactive and have repetitive habits, like rearing upright on their hind legs over and over. The researchers wondered what would happen if the two strains of mice were bred. Would the two mutations counterbalance one another? To their great surprise, that is exactly what happened. The shape and number of dendritic spines turned out to be normal, as was the transmission of nerve signals. So was the animals’ behavior. “Just by making two bad mouse mutants together, you make almost like a normal mouse,” Tonegawa says.

THE MEANING Using a drug to replicate the mutation-induced change in the PAK enzyme could potentially treat fragile X in humans. “Now we know the very unique target for producing a drug which may help to ameliorate the fragile X syndrome—a chemical compound which will inhibit PAK activity,” Tonegawa says. “But I want to emphasize that at this point we don’t have this drug.”

But the overall implications are even more profound, says New York University neuroscientist Eric Klann, because the researchers engineered the altered PAK gene to become active about three weeks after the mice were born. This hints that the course of fragile X in humans could be reversed after birth. “The thing that’s impressive is that morphological changes in the neurons that many labs have seen, both in fragile X patients as well as in mice that model fragile X, were reversed by changing the expression of this PAK gene. That’s very exciting.”